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Modulation of Membrane Lipid Receptors Explored via Multiscale Computer Simulations

Research output: Book/ReportDoctoral thesisCollection of Articles


Original languageEnglish
PublisherTampere University of Technology
Number of pages92
ISBN (Electronic)978-952-15-4301-2
ISBN (Print)978-952-15-4272-5
Publication statusPublished - 13 Dec 2018
Publication typeG5 Doctoral dissertation (article)

Publication series

NameTampere University of Technology. Publication
ISSN (Print)1459-2045


This work focuses on two lipid receptors known as GM1 and phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2). GM1 is a ganglioside present in the outer plasma membrane, sensing signals from the outside of the cell, while PI(4,5)P2 is an important phosphoinositide found in the inner leaflet of the plasma membrane. Due to their vital role in cellular life, studies of the lipid–lipid and lipid–protein interactions of these receptors have become an attractive venture for researchers. Nevertheless, despite a significant amount of work, the molecular details of these interactions have remained largely unknown due to the limited temporal and spatial resolution of the current experimental methods. Here we overcome this problem by using atomistic and coarse-grained molecular dynamics simulations applied to explore the structural and dynamical properties of these lipid receptors in various membranes.

In the first part of this Thesis, the functional properties of PI(4,5)P2 were studied through lipid–protein interactions between PI(4,5)P2, talin, and integrin. The simulations revealed a new means on how PI(4,5)P2 together with talin interferes with the stability of the integrin transmembrane domains, suggesting a new mechanism for the first steps of integrin activation.

The second part of this Thesis focuses on various mechanisms that can alter and regulate lipid receptor binding properties. First, the binding of cholera toxin to GM1 and the fluorescent analog of the receptor was examined. A clear difference in the behavior between the native and the labeled GM1 was observed. These results highlight the importance of artifacts that fluorescent labeling can cause. Second, the intracellular calcium was shown to affect the PI(4,5)P2 headgroup tilting and the related ligand binding. Importantly, these results were directly linked to cell signaling events through experimental findings observed by our collaborators. Finally, the fundamental question as to how the PI(4,5)P2 receptor is recognized only in the plasma membrane but not in the other cell compartments was explored. Enhanced ligand binding to cholesterol-rich PI(4,5)P2 membranes was found, suggesting that the steep cholesterol gradient along the secretory pathway in a cell may be a part of the machinery coordinating the specific cell organelle recognition.

Altogether, the Thesis provides novel insight on the function of lipid receptors, modulation of lipid–protein interactions, and highlights the added value gained by bridging scientific computing and novel computing tools with experimental science.

Field of science, Statistics Finland

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